The neurobiology of glucocerebrosidase-associated parkinsonism: a positron emission tomography study of dopamine synthesis and regional cerebral blood flow

+ Author Affiliations

1 Section on Molecular Neurogenetics, Medical Genetics Branch, NHGRI Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA
2 Section on Integrative Neuroimaging, Clinical Brain Disorders Branch, NIMH Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA
3 Office of the Clinical Director, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD 20892, USA

Correspondence to: Ellen Sidransky, 35 Convent Dr. Room 1A213, Bethesda, MD 20892-3708, USA E-mail: sidranse@mail.nih.gov

Received March 27, 2012.
Revision received April 25, 2012.
Accepted May 21, 2012.

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Summary

Mutations in GBA, the gene encoding glucocerebrosidase, the enzyme deficient in Gaucher disease, are common risk factors for Parkinson disease, as patients with Parkinson disease are over five times more likely to carry GBA mutations than healthy controls. Patients with GBA mutations generally have an earlier onset of Parkinson disease and more cognitive impairment than those without GBA mutations. We investigated whether GBA mutations alter the neurobiology of Parkinson disease, studying brain dopamine synthesis and resting regional cerebral blood flow in 107 subjects (38 women, 69 men). We measured dopamine synthesis with ¹⁸F-fluorodopa positron emission tomography, and resting regional cerebral blood flow with H₂¹⁵O positron emission tomography in the wakeful, resting state in four study groups: (i) patients with Parkinson disease and Gaucher disease (n = 7, average age = 56.6 ± 9.2 years); (ii) patients with Parkinson disease without GBA mutations (n = 11, 62.1 ± 7.1 years); (iii) patients with Gaucher disease without parkinsonism, but with a family history of Parkinson disease (n = 14, 52.6 ± 12.4 years); and (iv) healthy GBA-mutation carriers with a family history of Parkinson disease (n = 7, 50.1 ± 18 years). We compared each study group with a matched control group. Data were analysed with region of interest and voxel-based methods. Disease duration and Parkinson disease functional and staging scores were similar in the two groups with parkinsonism, as was striatal dopamine synthesis: both had greatest loss in the caudal striatum (putamen Ki loss: 44 and 42%, respectively), with less reduction in the caudate (20 and 18% loss). However, the group with both Parkinson and Gaucher diseases showed decreased resting regional cerebral blood flow in the lateral parieto-occipital association cortex and precuneus bilaterally. Furthermore, two subjects with Gaucher disease without parkinsonian manifestations showed diminished striatal dopamine. In conclusion, the pattern of dopamine loss in patients with both Parkinson and Gaucher disease was similar to sporadic Parkinson disease, indicating comparable damage in midbrain neurons. However, H₂¹⁵O positron emission tomography studies indicated that these subjects have decreased resting activity in a pattern characteristic of diffuse Lewy body disease. These findings provide insight into the pathophysiology of GBA-associated parkinsonism.